4-[4-[(R)-[1-[(Cyclopropylsulfonyl)-4-piperidinyl](3-fluorophenyl)methyl]-3(S)-methyl-1-piperazinyl]-1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-methylpiperidine (Formula 1 ) is disclosed U.S. Pat. No. 6,720,325 to Miller, incorporated herein by reference.

U.S. Pat. No. 6,720,325 discloses several novel antagonists of the CCR5 receptor which are useful for the treatment of AIDS and related HIV infections, including the compound of Formula 1. CCR5 receptors have also been reported to mediate cell transfer in inflammatory diseases such as arthritis, rheumatoid arthritis, atopic dermatitis, psoriasis, asthma and allergies, and inhibitors of such receptors are expected to be useful in the treatment of such diseases, and in the treatment of other inflammatory diseases or conditions such as inflammatory bowel disease, multiple sclerosis, solid organ transplant rejection and graft v. host disease.
Generally, pharmaceutical compounds are used as their pharmaceutically acceptable salts. This is true of CCR5 receptor antagonists such as the compound of Formula 1 too, which makes the preparation of pharmaceutically acceptable salts of such compounds quite important.
The compound of Formula 1 has two chiral centers and the absolute configurations of the chiral centers are controlled by the chemical synthesis. However, the compound of Formula 1 exists as a mixture of rotational isomers or rotamers. There are two rotamers (diastereomeric—relationship between the two) resulting from restricted rotation about the amide bond marked “a” in FIG. 1 and in Scheme 1. For present purposes, enantiomers of rotamer 1 are considered inclusively as rotamer 1 and the enantiomers of rotamer 2 are considered inclusively as rotamer 2 which will be apparent from the examples that follow. The two rotamers may be denoted as rotamers 1 and 2, in order of their elution from a HPLC column, rotamer 1 being the one eluting first, and rotamer 2 eluting second.
Scheme 1 illustrates rotation about the amide bond for two example rotamers:
While general synthetic approaches for salts typically yield a 1:1 ratio of the rotamers 1 and 2, it would be preferable to find methods of synthesis that would yield rotamer populations that are enriched in certain rotamers preferentially.
Pending U.S. application, Ser. No. 10/305,100 filed Nov. 26, 2002 describes the preparation of the pharmaceutical salts of bipiperidine compounds wherein the process results in the formation of certain enriched rotamer populations.
It would be preferable to find methods of synthesis for piperazine compounds that would yield rotamer populations that are enriched in certain rotamers preferentially. In view of the fact that the rotational barrier in amides is rather small, the period of rotation is consequently short and rapid interconversion takes place (see, for example, “Comprehensive Organic Chemistry”, Vol. 2, ed. I. O. Sutherland, Pergamon Press, New York, 1979, pages 987-988), novel methods are needed to achieve the desired preferentially enriched rotamer population.